Certain hexahydronaphthalene derivatives are known as potent inhibitors of the enzyme HMG-CoA reductase, the rate-controlling enzyme in the biosynthetic pathway for formation of cholesterol in the human body. Well known examples of these compounds are mevastatin (U.S. Pat. No. 3,983,140), lovastatin (U.S. Pat. No. 4,231,938), pravastatin (U.S. Pat. No. 4,346,227) and simvastatin (U.S. Pat. No. 4,444,784). All of these compounds are important pharmaceuticals and are widely used in hyperchotesterolaemic treatments.
Mevastatin, lovastatin and pravastatin are natural fermentation products which possess a 2-methylbutyrate side chain in the 8-position of their hexahydronaphthalene ring system. It has been proven that products possessing a 2,2-dimethylbutyrate side chain in the same position (e.g. simvastatin (formula (A)) are even more active. Simvastatin is however, not naturally occurring. ##STR2##
One route to introduce an additional .alpha.-methyl group to the 8-acyl side chain of lovastatin (formula (B)) or its analogues is disclosed in U.S. Pat. No. 4,444,784. This process involves indirect methylation of the said side chain through several chemical steps: deesterification of the whole 2-methylbutyrate side chain, protection of the 4-hydroxy group in the pyranone ring by a tert-butyldimethylsilyl protective group, reesterification of the protected lactone with 2,2-dimethylbutyric acid, and deprotection of the hydroxy group of the pyranone ring. This procedure involves multiple chemical reactions with a low overall yield.
Another route, based on direct methylation of the 8-acyl side chain of lovastatin and its analogues is disclosed in U.S. Pat. No. 4,582,915. Direct methylation of the 2-methylbutyrate side chain of lovastatin is achieved, after conversion to an alkali metal salt thereof, using a methylhalide in the presence of a strong base (metal alkylamide). Such a process exhibits disadvantages including low conversion, resulting in contamination of the product by a significant concentration of unconverted starting material and relatively high concentration of by-products.
The problems of low yields and poor quality of the final product have been addressed in a process disclosed in U.S. Pat. No. 4,820,850. This procedure comprises:
a) treatment of lovastatin with butylamine to achieve ring-opening of the lactone, followed by the protection of the hydroxyl-groups therein with tert-butyldimethylsilyl chloride; PA1 b) treatment of the obtained protected intermediate with an alkalimetal amide followed by contact with alkylhalide to add an alkyl group to the 2-position of the butyrate side chain; PA1 c) removal of the silyl protective groups by an acid, preferably hydrofluoric acid; PA1 d) treatment with dilute base to hydrolyse the alkylamide; and PA1 e) heating of the resulting carboxylate salt in a hydrocarbon solvent to reform the lactone. PA1 wherein R.sup.1 represents hydrogen or methyl and R.sup.2 represents a straight or branched chain alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an aralkyl group having 1 to 6 carbon atoms in the alkyl chain; PA1 wherein R.sup.1 and R.sup.2 are as defined above in formula (II), R.sup.3 and R.sup.4 each independently represents an alkyl group, an ether group, a thioether group, an aryl group, an aralkyl group, an alkenyl group, a cyclic ether group, or a cyclic thioether group, and R.sup.5 and R.sup.6 each independently represents hydrogen, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, or an ether group. PA1 R.sup.7 is methyl or ethyl and R.sup.3 -R.sup.6 are as defined above. The compounds of formula (III), (IV), (VII), and (VIII) are a second embodiment of the invention. PA1 lovastatin ethylamide bis-tetrahydropyran-2-ylether (compound (III), wherein R.sup.1 =methyl, R.sup.2 -ethyl, R.sup.3 =R.sup.4 =tetrahydropyran-2-yl) PA1 lovastatin n-butylamide bis-tetrahydropyran-2-ylether (compound (III), wherein R.sup.1 =methyl, R.sup.2 =n-butyl, R.sup.3 =R.sup.4 =tetrahydropyran-2-yl) PA1 lovastatin ethylamide acetonide (compound (VII) wherein R.sup.1 =methyl, R.sup.2 =ethyl, R.sup.5 =R.sup.6 =methyl) PA1 lovastatin butylamide acetonide (compound (VII) wherein R.sup.1 =methyl, R.sup.2 =n-butyl, R.sup.5 =R.sup.6 =methyl). PA1 Simvastatin ethylamide bis-tetrahydropyran-2-ylether (compound (IV), wherein R.sup.1 =methyl, R.sup.2 =ethyl, R.sup.3 =R.sup.4 =tetrahydropyran-2-yl, R.sup.7 =methyl) PA1 Simvastatin n-butylamide bis-tetrahydropyran-2-ylether (compound (IV), wherein R.sup.1 =methyl, R.sup.2 =n-butyl, R.sup.3 =R.sup.4 =tetrahydropyran-2-yl, R.sup.7 =methyl) PA1 Simvastatin ethylamide acetonide (compound (VIII) wherein R.sup.1 =methyl, R.sup.2 =ethyl, R.sup.5 =R.sup.6 =R.sup.7 =methyl) PA1 Simvastatin butylamide acetonide (compound (VIII) wherein R.sup.7 =methyl, R.sup.2 =n-butyl, R.sup.5 =R.sup.6 =R.sup.7 =methyl).
Another direct methylation process is described in U.S. Pat. No. 5,393,893. Here, a lovastatin-C.sub.3 -C.sub.7 -alkyl amide, cycloalkylamide or aralkylamide is prepared, the hydroxyl-groups thereof are protected with a phenylboronic acid and the resulting intermediate is further reacted with an alkylhalide in the presence of a base to introduce the alkyl moiety into the butyrate side chain. The subsequent steps leading to simvastatin involve, similarly as in the preceding patent, the removal of the protective groups, hydrolysis of the alkylamide and relactonization to form simvastatin.
As apparent, the above synthetic routes, which involve the step of direct methylation, differ from each other namely by the nature of OH-protective groups in the reaction intermediates. These protected intermediates can be characterized by the presence of a C--O--Si-- or C--O--B-- linkage in their molecules.
However, in these known routes, the intermediates are quite unstable towards environmental hydrolysis and unstable towards strongly alkaline conditions during the methylation. As a result, undesirable amounts of by-products are formed during the synthesis. To obtain a product having the desired pharmaceutical quality, these by-products have to be removed by additional purification methods which lowers the overall yield and increases cost. Furthermore, the protecting agents used are economically undesirable.